During the decade, over a thousand analogs of the luteinizing hormone releasing hormone (LHRH) have been internationally synthesized, some of which were significant agonists, "super-agonists" or antagonists. The biological goal of antagonists of LHRH is effective and potent antiovulatory activity toward control of conception. Folkers, Humphries and Bowers [Z. Naturforsch. 37b, 246-249 (1982)] critiqued the evolution of design and achievement of inhibitors of LHRH as inhibitors of ovulation, based on the research of many investigators. A recent significant advance in sequence changes to increase antiovulatory potency was reported by Coy et al. [Endocrinology 110, 1445-1447 (1982)] on the--"unexpectedly favorable outcome"--of introducing D-Lys and D-Arg in position 6. D-Arg.sup.6 was superior to D-Lys.sup.6 in a pair, and [N-Ac-pCl-D-Phe.sup.1,2,D-Trp.sup.3,D-Arg.sup.6,D-Ala.sup.10 ]-LHRH caused 100% inhibition of ovulation at 1.5 .mu.g and 40% at 0.75 .mu.g.
Nestor et al. [J. Med. Chem. 25, 795-801 (1982)] synthesized and bioassayed several very hydrophobic analogs of LHRH for super-agonistic activity. They found that .beta.-(2-naphthyl)-D-.alpha.-alanine, when introduced into position 6 of LHRH, resulted in one of the most potent LHRH agonists ever reported. Such an agonist was comparable to or more potent than the widely studied LHRH agonist having D-Trp.sup.6.
Although a diversity of agonists and antagonists related to LHRH, which have D-tryptophan in position 3 and/or 6, have been far greater investigated than analogs having a naphthyl-alanine, the bicyclic nature of the indole and naphthalene nucleus with and without a nitrogen atom, was a basis for our initiation of the synthesis of several heterocyclic analogs of tryptophan and naphthylalanine, in the D-configuration, and the insertion of these heterocyclic amino acids into analogs of LHRH. Initially, analogs containing quinolylalanines and pyridylalanines were synthesized, because these amino acids combine basicity, aromaticity and hydrophilicity in the same molecule. We report the results of the synthesis and bioassay of analogs of LHRH containing pyridyl-alanyl moieties.